Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study.

BACKGROUND: Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma. METHODS: We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 × 106 (dose level 1) or 100 × 106 (dose level 2, DL2) chimeric antigen receptor-positive T cells. The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198. FINDINGS: Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis). INTERPRETATION: A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable. FUNDING: Juno Therapeutics, a Bristol-Myers Squibb Company.

[The organization of pharmaceutical care in the territory has no effect on patient compliance: the case of direct or account distribution of antidiabetics]. / L'organizzazione dell'assistenza farmaceutica sul territorio non ha effetto sulla compliance del paziente: il caso della distribuzione diretta o per conto degli antidiabetici.

OBJECTIVES: the objective of the study is to assess the effect of the delivery channel on adherence, persistence and potential wastage of new antidiabetic drugs. DESIGN: longitudinal descriptive observational study. New users were defined as subjects who received a first prescription of drugs belonging to the antidiabetic category in the period between 01.01.2021 and 31.03.2021 (index date) and who did not receive prescriptions for drugs belonging to the same category in the previous 6 months, as of 01.07.2020. Each subject was followed for a follow-up period of 9 months. SETTING AND PARTICIPANTS: the study examined adherence and persistence to treatment with antidiabetic drugs in Italy for patients aged>=45 years (information flow of pharmaceutical services performed in direct distribution and on behalf established by Ministerial Decree Health 31 July, 2007). MAIN OUTCOME MEASURES: adherence to treatment measured by the Medication Possession Rate (MPR) indicator, defined as the ratio of the number of days of therapy dispensed (calculated from DDDs) to the number of days covered by drug therapy; persistence to treatment defined as "time elapsed between the initiation and discontinuation of a prescribed drug therapy" estimated by as "time elapsed between the initiation and discontinuation of a drug therapy" estimated by Cox semi-parametric model; difference in terms of waste understood as the number of packs not fully used by non-persistent subjects. RESULTS: the analysis showed that there were no significant differences between the dispensing channels in adherence, persistence, and medication wastage (defined as the distribution of packages to non-persistent patients). Specifically, it turns out that the percentage of highly adherent subjects at 9 months is 62.2 for those on treatment in the direct distribution channel and 64.6 for those on treatment with account distribution; with regard to persistence at 9 months, however, a difference of less than one percentage point was observed between the two channels. Although this study focused on a specific therapeutic class, the results can be generalised to other high-prevalence chronic diseases. However, some limitations of the study were pointed out, such as the difficulty of replicating the results due to the variability of data depending on the drug category and the time period considered. CONCLUSIONS: the choice of distribution channel for antidiabetic drugs should not be based on adherence or persistence to treatment, but on other determinants such as cost of service and logistical complications.

Der p 23-specific IgE response throughout childhood and its association with allergic disease: A birth cohort study.

BACKGROUND: The Dermatophagoides pteronyssinus molecule Der p 23 is a major allergen whose clinical relevance has been shown in cross-sectional studies. We longitudinally analysed the trajectory of Der p 23-specific IgE antibody (sIgE) levels throughout childhood and youth, their early-life determinants and their clinical relevance for allergic rhinitis and asthma. METHODS: We obtained sera and clinical data of 191 participants of the German Multicentre Allergy Study, a prospective birth cohort. Serum samples from birth to 20 years of age with sIgE reactivity to Der p 23 in a customised semiquantitative microarray were newly analysed with a singleplex quantitative assay. Early mite exposure was assessed by measuring the average content of Der p 1 in house dust at 6 and 18 months. RESULTS: Der p 23-sIgE levels were detected at least once in 97/191 participants (51%). Prevalence of Der p 23 sensitisation and mean sIgE levels increased until age 10 years, plateaued until age 13 years and were lowest at age 20 years. Asthma, allergic rhinitis (AR) and atopic dermatitis (AD) were more prevalent in Der p 23-sensitised children, including those with monomolecular but persistent sensitisation (11/97, 11%). A higher exposure to mites in infancy and occurrence of AD before 5 years of age preceded the onset of Der p 23 sensitisation, which in turn preceded a higher incidence of asthma. CONCLUSIONS: Der p 23 sensitisation peaks in late childhood and then decreases. It is preceded by early mite exposure and AD. Asthma and AR can occur in patients persistently sensitised to Der p 23 as the only mite allergen, suggesting the inclusion of molecular testing of Der p 23-sIgE for subjects with clinical suspicion of HDM allergy but without sIgE to other major D.pt. allergens.

@IT2020: An innovative algorithm for allergen immunotherapy prescription in seasonal allergic rhinitis.

BACKGROUND: Allergen immunotherapy (AIT) is the only disease-modifying treatment in patients with seasonal allergic rhinoconjunctivitis (SAR). Its efficacy depends on the precise identification of the triggering allergen. However, diagnostics based on retrospective clinical history and sensitization to whole extracts (SWE) often leads to equivocal results. OBJECTIVES: To assess the usability and impact of a recently established algorithm for a clinical decision support system (@IT2020-CDSS) for SAR and its diagnostic steps [anamnesis, SWE (skin prick test or serum IgE), component resolved diagnosis, CRD, and real-time digital symptom recording, eDiary] on doctor's AIT prescription decisions. METHODS: After educational training on the @IT2020-CDSS algorithm, 46 doctors (18 allergy specialists, AS, and 28 general practitioners, GP) expressed their hypothetical AIT prescription for 10 clinical index cases. Decisions were recorded repeatedly based on different steps of the algorithm. The usability and perceived impact of the algorithm were evaluated. RESULTS: The combined use of CRD and an eDiary increased the hypothetical AIT prescriptions, both among AS and GP (p < .01). AIT prescription for pollen and Alternaria allergy based on anamnesis and SWE was heterogeneous but converged towards a consensus by integrating CRD and eDiary information. Doctors considered the algorithm useful and recognized its potential in enhancing traditional diagnostics. CONCLUSIONS AND CLINICAL IMPLICATIONS: The implementation of CRD and eDiary in the @IT2020-CDSS algorithm improved consensus on AIT prescription for SAR among AS and GP. The potential usefulness of a CDSS for aetiological diagnosis of SAR and AIT prescription in real-world clinical practice deserves further investigation.

IgE antibody repertoire in nasal secretions of children and adults with seasonal allergic rhinitis: A molecular analysis.

BACKGROUND: There is growing interest both in testing IgE in nasal secretions (NS) and in molecular diagnosis of seasonal allergic rhinitis (SAR). Yet, the reliability of nasal IgE detection with the newest molecular assays has never been assessed in a large cohort of pollen allergic patients. OBJECTIVE: To investigate with microarray technology and compare the repertoires of specific IgE (sIgE) antibodies in NS and sera of a large population of children and adults with SAR. METHODS: Nasal secretions were collected with an absorbent device (Merocel 2000® , Medtronic) and a minimal dilution procedure from 90 children and 71 adults with SAR. Total IgE (tIgE) (ImmunoCAP, Thermo Fisher Scientific (TFS)) and sIgE antibodies against 112 allergen molecules (ISAC-112, TFS) were measured in NS and serum. RESULTS: Nasal sIgE was detectable in 68.3% of the patients. The detected nasal sIgE antibodies recognized airborne (88%), vegetable (10%), and animal food or other (<1%) allergen molecules. The prevalence and average levels of sIgE in NS and serum were highly interrelated at population level. A positive nasal sIgE antibody to a given molecule predicted the detection of the same antibody in the patient's serum with a specificity of 99.7% and a sensitivity of 40%. CONCLUSIONS: The concentration of sIgE is much lower in nasal secretions than in the serum. sIgE assays with very high analytical sensitivity and sampling methods with minimal dilution will be therefore needed to validate nasal secretions as alternative to serum in testing the sIgE repertoire.

Drug discontinuation in pregnant women with psoriasis: The PSO-MOTHER cohort study.

PURPOSE: To analyse the drug use pattern in women with psoriasis before, during and after pregnancy. METHODS: All children born (2009-2016) in a central Italian region (Lazio) to mothers with a diagnosis of psoriasis were identified. Drug use patterns (biologicals, systemic, and topical), and discontinuation and switching of drug therapies before, during, and after pregnancy were studied. Findings were compared with data from a population exposed to similar drug therapies (eg, antirheumatic drugs). RESULTS: Among 3499 deliveries by women affected by psoriasis, 1876 (53.6%) were diagnosed with this condition before the Last Menstrual Period (LMP). Of these, 525 (27.9%) had at least one drug prescription for psoriasis therapy during 6 months before LMP. For each class of drugs considered, there was a general decrease in its use during pregnancy. Considering the two trimesters preceding LMP and the three trimesters of pregnancy, the following percentages of prescriptions were observed: from 10.5% to 0% for biologicals, 7.2% to 2.5% for the conventional systemic drugs, and 51.1% to 9.4% for the topical treatments. After delivery, previous treatments were resumed. Similar results were observed for rheumatoid arthritis, a chronic condition. CONCLUSIONS: Majority of drugs come with warnings regarding potential embryo-fetotoxicity, which might play a role in the decision to continue treatments during pregnancy. According to our study pregnancy appears to have a significant influence on drug prescriptions of different pharmacological treatments for psoriasis.

Adherence to Prescribed E-Diary Recording by Patients With Seasonal Allergic Rhinitis: Observational Study.

BACKGROUND: Complete diagnosis and therapy of seasonal allergic rhinoconjunctivitis require evidence that exposure to the sensitizing pollen triggers allergic symptoms. Electronic clinical diaries, by recording disease severity scores and pollen exposure, can demonstrate this association. However, patients who spontaneously download an e-diary app show very low adherence to their recording. OBJECTIVE: The objective of our study was to assess adherence of patients with seasonal allergic rhinitis to symptom recording via e-diary explicitly prescribed by an allergist within a blended care approach. METHODS: The @IT-2020 project is investigating the diagnostic synergy of mobile health and molecular allergology in patients with seasonal allergic rhinitis. In the pilot phase of the study, we recruited Italian children (Rome, Italy) and adults (Pordenone, Italy) with seasonal allergic rhinitis and instructed them to record their symptoms, medication intake, and general conditions daily through a mobile app (Allergy.Monitor) during the relevant pollen season. RESULTS: Overall, we recruited 101 Italian children (Rome) and 93 adults (Pordenone) with seasonal allergic rhinitis. Adherence to device use slowly declined during monitoring in 3 phases: phase A: first week, ≥1267/1358, 90%; phase B: second to sixth week, 4992/5884, 80% to 90%; and phase C: seventh week onward, 2063/2606, 70% to 80%. At the individual level, the adherence assessed in the second and third weeks of recording predicted with enough confidence (Rome: Spearman ρ=0.75; P<.001; Pordenone: ρ=0.81; P<.001) the overall patient adherence to recording and was inversely related to postponed reporting (ρ=-0.55; P<.001; in both centers). Recording adherence was significantly higher during the peak grass pollen season in Rome, but not in Pordenone. CONCLUSIONS: Adherence to daily recording in an e-diary, prescribed and motivated by an allergist in a blended care setting, was very high. This observation supports the use of e-diaries in addition to face-to-face visits for diagnosis and treatment of seasonal allergic rhinitis and deserves further investigation in real-life contexts.

A new molecular multiplex IgE assay for the diagnosis of pollen allergy in Mediterranean countries: A validation study.

BACKGROUND: The identification of the primary sensitizing pollen is difficult in Southern European patients with Seasonal Allergic Rhinitis (SAR) if sensitized to various pollen sources with overlapping seasonality. A more precise diagnosis is obtained by IgE assays to allergen molecules, currently available as singleplex or microarrays. OBJECTIVES: To test the analytical performance of a multi-parameter immunoblot molecular "Pollen Test" specifically designed to test IgE antibodies to pollen extracts and molecules clinically relevant in Southern Europe. METHODS: Sera were obtained from 101 children and 98 adults with SAR and tested with a customized multiplex immunoblot assay (EUROLINE Southern European Pollen Profile [ESEP]; EUROIMMUN AG, Luebeck, Germany) containing a comprehensive panel of allergen extracts and molecules. ESEP's outcomes were then compared in selected sera (ESEP positive to negative = 2:1) with those of singleplex IgE assays (ImmunoCAP; ThermoFisher Scientific, Uppsala, Sweden). For each of the examined reagents, qualitative (sensitivity, specificity, accuracy), semi-quantitative (classes) and quantitative (Spearman's rank correlation, Bland-Altmann plots) comparisons were performed. RESULTS: Compared to ImmunoCAP, cumulative ESEP's sensitivity and specificity were 87% (95% CI 84%-90%) and 88% (83%-93%) for extracts and 99% (98%-100%) and 87% (83%-91%) for molecules. Cohen's kappa coefficients (κC ) ranged for extracts from 0.18 (Pellitory) to 0.50 (Cypress) and for molecules from 0.21 (Ole e 1) to 0.68 (Phl p 7). The quantitative outcomes of the two diagnostic tests were highly correlated, with Spearman's rank correlation coefficients always exceeding 0.80. Bland-Altmann plots showed a tendency of ESEP to overestimate serum specific IgE levels, when compared to ImmunoCAP. CONCLUSIONS AND CLINICAL RELEVANCE: Sensitivity and specificity of ESEP in testing serum IgE antibodies against pollen allergen extracts and molecules, in Italian patients with SAR, both exceeded 85%. The advantages and limitations of a multiplex customized immunoblot assay, in the routine clinical use of molecular diagnostics in Southern European pollen allergic patients, deserve to be tested.

Early molecular biomarkers predicting the evolution of allergic rhinitis and its comorbidities: A longitudinal multicenter study of a patient cohort.

BACKGROUND: Pollen-related seasonal allergic rhinoconjunctivitis (SAR) is a very frequent pediatric disease in Westernized countries. Risk factors and disease phenotypes have been thoroughly examined in several cross-sectional studies. By contrast, only a few studies have examined disease evolution in patient cohorts. We investigated predictive biomarkers of disease evolution in a large cohort of children with SAR. METHODS: During 2015-2017 (follow-up), we re-examined 401 patients from those enrolled in 2009-2011 (baseline) by the "Panallergens in Pediatrics" study, a large multicenter survey of Italian children with SAR. Information on clinical history (standard questionnaire, AllergyCARD®; TPS, Italy) and skin prick tests for inhalant and foods extracts (ALK-Abelló, Hørsholm, Denmark) was acquired as at baseline visit. Evolution in clinical and sensitization data of patients was analyzed over time, as well as their association with the main baseline characteristics and atopy risk factors. RESULTS: The average age of participants was 10.4 ± 3.4 years at baseline and 16.2 ± 3.6 years at follow-up. SAR persisted in 93.3% of patients at follow-up and became more frequently associated with asthma (from 36.7% at baseline to 48.6% at follow-up) and oral allergy syndrome (OAS, from 23.4% to 37.7%). Compared to baseline, the prevalence of skin sensitization to some pollens (Phleum pratense, Corylus avellana, Platanus acerifolia, Artemisia vulgaris) and vegetables (hazelnut, wheat, and apple) significantly decreased at follow-up. Earlier onset of SAR and polysensitization at baseline were associated with incident asthma at follow-up. The presence at baseline of serum IgE to the following allergen molecules was identified as biomarkers of clinical evolution: (a) Phl p 1, for persistence of SAR; (b) Phl p 5, for persistence of both rhinitis and asthma; (c) Pru p 3, for new onset of asthma; (d) Bet v 1, for persistence of OAS. CONCLUSIONS: Seasonal allergic rhinoconjunctivitis is clinically heterogeneous in its evolution from childhood to adolescence. The detection of serum IgE to specific molecules (Phl p 1, Phl p 5, Bet v 1, Pru p 3) may be useful as biomarkers to predict SAR persistence and future onset of comorbidities, such as asthma and/or OAS.

Evolution and predictive value of IgE responses toward a comprehensive panel of house dust mite allergens during the first 2 decades of life.

BACKGROUND: The evolution of the IgE response to the numerous allergen molecules of Dermatophagoides pteronyssinus is still unknown. OBJECTIVES: We sought to characterize the evolutionary patterns of the IgE response to 12 molecules of D pteronyssinus from birth to adulthood and to investigate their determinants and clinical relevance. METHODS: We investigated the clinical data and sera of 722 participants in the German Multicenter Allergy Study, a birth cohort started in 1990. Diagnoses of current allergic rhinitis (AR) related to mite allergy and asthma were based on yearly interviews at the ages of 1 to 13 years and 20 years. IgE to the extract and 12 molecules of D pteronyssinus were tested by means of ImmunoCAP and microarray technology, respectively, in sera collected at ages 1, 2, 3, 5, 6, 7, 10, 13, and 20 years. Exposure to mites at age 6 and 18 months was assessed by measuring Der p 1 weight/weight concentration in house dust. RESULTS: One hundred ninety-one (26.5%) of 722 participants ever had IgE to D pteronyssinus extract (≥0.35 kUA/L). At age 20 years, their IgE recognized most frequently Der p 2, Der p 1, and Der p 23 (group A molecules; prevalence, >40%), followed by Der p 5, Der p 7, Der p 4, and Der p 21 (group B molecules; prevalence, 15% to 30%) and Der p 11, Der p 18, clone 16, Der p 14, and Der p 15 (group C molecules; prevalence, <10%). IgE sensitization started almost invariably with group A molecules and expanded sequentially first to group B and finally to group C molecules. Early IgE sensitization onset, parental hay fever, and higher exposure to mites were associated with a broader polymolecular IgE sensitization pattern. Participants reaching the broadest IgE sensitization stage (ie, ABC) had significantly higher risk of mite-related AR and asthma than unsensitized participants. IgE to Der p 1 or Der p 23 at age 5 years or less predicted asthma at school age. CONCLUSIONS: Parental hay fever and early exposure to D pteronyssinus allergens promote IgE polysensitization to several D pteronyssinus molecules, which in turn predicts current mite-related AR and current/future asthma. These results might inspire predictive algorithms and prevention strategies against the progression of IgE sensitization to mites toward AR and asthma.

Growth curves of "normal" serum total IgE levels throughout childhood: A quantile analysis in a birth cohort.

BACKGROUND: Previous studies of serum total IgE (t-IgE) were not able to discriminate well-enough atopic from non-atopic subjects, that is, with or without serum-specific IgE antibodies to allergens. OBJECTIVES: To model growth curves of the total IgE levels in children without atopic sensitization (hereafter defined as "normal" t-IgE levels) and to test their usefulness in predicting atopic sensitization. METHODS: The German Multicentre Allergy Study (MAS), a birth cohort with 1314 recruited newborns, began in 1990 and examined the participants until age 20 years. Total and specific IgE (t-IgE, s-IgE) were analyzed with a fluorescent enzyme immunoassay ImmunoCAP (TFS, Sweden) at ages 1, 2, 3, 5, 6, 7, 10, 13, and 20 years. Participants were classified as "never atopic" if all their available serum samples had negative response (cutoff: <0.35 kUA /L) for s-IgE to the nine common foodborne and airborne allergenic extracts (milk, egg, soy, wheat, house dust mite, cat, dog, birch, and grass) tested in the MAS birth cohort. By contrast, participants were defined as atopic if they had, for at least at one available serum sample, s-IgE≥0.35 kUA /L to at least one allergenic extract tested. The evolution of t-IgE levels in the "never atopic" children was described by growth curves, estimated by exploiting a quantile regression model. A "reference" percentile, based on the t-IgE value measured at age 5 years, was assigned to each child with no IgE sensitization at that age. Upward deviations from the own "reference" quantile of t-IgE in atopic and "never atopic" children were calculated and a ROC analysis was used to identify the best cutoff point for predicting atopic sensitization. RESULTS: Overall, 1113 of 1314 children were included in this analysis. Of these, 469 were "never atopic" and 644 atopic. Quantile trajectories of t-IgE levels in "never atopic" subjects were stable from 5 years of age, increased to a plateau at age 10-13 years, and decreased slightly afterward. The onset of atopic s-IgE responses was characterized by an upward deviation of serum t-IgE levels from their "reference" trajectory. T-IgE quantiles predicted the onset of atopy with high efficiency (AUC>80%). ROC analysis showed that deviations from the t-IgE level "reference" quantile above 0.32, 0.41, 0.42, 0.30, and 0.58 kU/L (log-units) at 6, 7, 10, 13, and 20 years of age, respectively, predicted an atopic sensitization. CONCLUSION: The growth curves of "normal" serum t-IgE concentrations were estimated in "never atopic" children; for each individual who was non-atopic at 5 years of age a "reference" quantile was identified that represented the individual's "normal" level of t-IgE production. Upward deviations of observed t-IgE levels from the own "reference" quantile, from 6 to 20 years of age, predicted at each year the occurrence of atopic sensitization. CLINICAL IMPLICATIONS: The trajectory of t-IgE levels can be elaborated since age 5 years in non-atopic children. A child whose t-IgE levels are consistently higher than those predicted by his/her growth curve may have developed atopic sensitization.

Comparison of six disease severity scores for allergic rhinitis against pollen counts a prospective analysis at population and individual level.

BACKGROUND: Many different symptom (medication) scores are nowadays used as measures of allergic rhinoconjunctivitis severity in individual patients and in clinical trials. Their differences contribute to the heterogeneity of the primary end-point in meta-analyses, so that calls for symptom (medication) score harmonization have been launched. OBJECTIVE: To prospectively compare six different severity scores for allergic rhinitis (AR) against pollen counts at both population and individual levels. METHODS: Two groups of children with seasonal AR and grass pollen sensitization were recruited in Ascoli, Italy (n = 76) and Berlin, Germany (n = 29). Symptoms and drug intake were monitored daily for 40 and 30 days of the grass pollen season in 2011 (Ascoli) and 2013 (Berlin), respectively, through an Internet-based platform (AllergyMonitor(™) , TPS Production srl, Rome, Italy). From the gathered data, the informatics platform automatically generated one symptom score (RTSS) and five symptom-medication scores (RC-ACS(©) , ACS, RTSS[LOCF], RTSS[WC] and AdSS). Values were then statistically normalized for reciprocal comparison and matched against the daily variations of local grass pollen counts (Spearman's rank correlation). RESULTS: The grass pollen counts were higher in Ascoli than in Berlin (peak values 194 vs. 59 grains/m(3) ). At population level, the trajectories of the normalized average values of the six scores differed only slightly in both studies and correlated well with the pollen counts (ranges r(2) : 0.38-0.50 in Ascoli, 0.41-0.56 in Berlin). By contrast, in individual patients, trajectories of different scores were often quite heterogeneous. The RTSS[WC] had a very low discriminatory power and generated in many patients long, flat horizontal segments. CONCLUSIONS: Disease severity scores for seasonal AR, as evaluated via an Internet-based platform, tend to provide similar results at population level but can often produce heterogeneous slopes in individual patients. The choice of the disease severity score might have only a low impact on the outcome of a very large clinical trial, but it may be crucial in the management of individual patients.

Graft-versus-leukemia effect of HLA-haploidentical central-memory T-cells expanded with leukemic APCs and modified with a suicide gene.

Allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)-haploidentical family donor (haplo-HSCT) is a readily available and potentially curative option for high-risk leukemia. In haplo-HSCT, alloreactivity plays a major role in the graft-versus-leukemia (GVL) effect, which, however, is frequently followed by relapse due to emerging leukemic cell variants that have lost the unshared HLA haplotype as a mechanism of immune escape. We report that stimulation of HLA-haploidentical donor T lymphocytes with leukemic antigen-presenting cells (L-APCs) expands a population of leukemia-reactive T cells, which, besides alloreactivity to unshared HLAs, contain leukemia-associated specificities restricted by shared HLAs. According to a preferential central-memory (T(CM)) phenotype and to high interleukin (IL)-7Rα expression, these T cells persist in vivo and sustain a major GVL effect in a clinically relevant xenograft model. Moreover, we demonstrate that modifying L-APC-expanded T cells to express the herpes simplex virus thymidine kinase (HSV-tk) suicide gene enables their elimination with the prodrug ganciclovir (GCV), therefore providing a safety switch in case of graft-versus-host disease (GVHD). These results warrant the clinical investigation of L-APC-expanded T cells modified with a suicide gene in the setting of haplo-HSCT.

Antihypertensive therapy during pregnancy: the prescription pattern in Italy.

Drug use during pregnancy should be evidence-based and favor the safest and most appropriate prescription. The Italian Medicines Agency (AIFA) coordinates a network focusing on monitoring medication use in pregnancy. Hypertensive disorders are common medical complication of pregnancy and antihypertensive therapy is prescribed to reduce the risk of adverse feto-maternal complications. The objective of this study is to highlight the prescription pattern of antihypertensive drugs before pregnancy, during pregnancy and in the postpartum period in Italy and to evaluate their use with a specific attention to the prescription pattern of drugs considered safe during pregnancy. A multi-database cross-sectional population study using a Common Data Model (CDM) was performed. We selected all women aged 15-49 years living in eight Italian regions who gave birth in hospital between 1 April 2016 and 31 March 2018. In a cohort of 449.012 women, corresponding to 59% of Italian deliveries occurred in the study period, the prevalence of prescription of antihypertensive drugs in the pre-conceptional period was 1.2%, in pregnancy 2.0% and in the postpartum period 2.9%. Beta-blockers were the most prescribed drugs before pregnancy (0.28%-0.30%). Calcium channel blockers were the most prescribed drugs during pregnancy, with a prevalence of 0.23%, 0.33%, 0.75% in each trimester. Alfa-2-adrenergic receptor agonists were the second most prescribed during pregnancy with a prevalence of 0.16%, 0.26% and 0.55% in each trimester. The prescription of drugs contraindicated during pregnancy was below 0.5%. Only a small percentage of women switched from a contraindicated drug to a drug compatible with pregnancy. The analysis showed little variability between the different Italian regions. In general, the prescription of antihypertensive drugs in the Italian Mom-Network is coherent with the drugs compatible with pregnancy.

Robust and cost effective expansion of human regulatory T cells highly functional in a xenograft model of graft-versus-host disease.

The low frequency of naturally occurring regulatory T cells (nTregs) in peripheral blood and the suboptimal protocols available for their ex vivo expansion limit the development of clinical trials based on the adoptive transfer of these cells. We have, therefore, generated a simplified, robust and cost-effective platform for the large-scale expansion of nTregs using a gas permeable static culture flask (G-Rex) in compliance with Good Manufacturing Practice. More than 10(9) putative Tregs co-expressing CD25 and CD4 molecules (92 ± 5%) and FoxP3 (69 ± 19%) were obtained within 21 days of culture. Expanded Tregs showed potent regulatory activity in vitro (80 ± 13% inhibition of CD8(+) cell division) and in vivo (suppression or delay of graft-versus-host disease in a xenograft mouse model) indicating that the cost-effective and simplified production of nTregs we propose will facilitate the implementation of clinical trials based on their adoptive transfer.

Rapidly generated multivirus-specific cytotoxic T lymphocytes for the prophylaxis and treatment of viral infections.

Severe and fatal viral infections remain common after hematopoietic stem cell transplantation. Adoptive transfer of cytotoxic T lymphocytes (CTLs) specific for Epstein-Barr virus (EBV), cytomegalovirus (CMV), and adenoviral antigens can treat infections that are impervious to conventional therapies, but broader implementation and extension to additional viruses is limited by competition between virus-derived antigens and time-consuming and laborious manufacturing procedures. We now describe a system that rapidly generates a single preparation of polyclonal (CD4(+) and CD8(+)) CTLs that is consistently specific for 15 immunodominant and subdominant antigens derived from 7 viruses (EBV, CMV, Adenovirus (Adv), BK, human herpes virus (HHV)-6, respiratory syncytial virus (RSV), and Influenza) that commonly cause post-transplant morbidity and mortality. CTLs can be rapidly produced (10 days) by a single stimulation of donor peripheral blood mononuclear cells (PBMCs) with a peptide mixture spanning the target antigens in the presence of the potent prosurvival cytokines interleukin-4 (IL4) and IL7. This approach reduces the impact of antigenic competition with a consequent increase in the antigenic repertoire and frequency of virus-specific T cells. Our approach can be readily introduced into clinical practice and should be a cost-effective alternative to common antiviral prophylactic agents for allogeneic hematopoietic stem cell transplant (HSCT) recipients.

Antidiabetic Therapy during Pregnancy: The Prescription Pattern in Italy.

Pregestational and gestational diabetes mellitus are relevant complications of pregnancy, and antidiabetic drugs are prescribed to obtain glycemic control and improve perinatal outcomes. The objective of this study was to describe the prescription pattern of antidiabetics before, during and after pregnancy in Italy and to evaluate its concordance with the Italian guideline on treatment of diabetes mellitus. A multi-database cross-sectional population study using a Common Data Model was performed. In a cohort of about 450,000 women, the prescribing profile of antidiabetics seemed to be in line with the Italian guideline, which currently does not recommend the use of oral antidiabetics and non-insulin injection, even if practice is still heterogeneous (up to 3.8% in the third trimester used oral antidiabetics). A substantial variability in the prescription pattern was observed among the Italian regions considered: the highest increase was registered in Tuscany (4.2%) while the lowest was in Lombardy (1.5%). Women with multiple births had a higher proportion of antidiabetic prescriptions than women with singleton births both in the preconception period and during pregnancy (1.3% vs. 0.7%; 3.4% vs. 2.6%) and used metformin more frequently. The consumption of antidiabetics in foreign women was higher than Italians (second trimester: 1.8% vs. 0.9%, third trimester: 3.6% vs. 1.8%).

Monitoring medicine prescriptions before, during and after pregnancy in Italy.

BACKGROUND: The use of medications during pregnancy is a common event worldwide. Monitoring medicine prescriptions in clinical practice is a necessary step in assessing the impact of therapeutic choices in pregnant women as well as the adherence to clinical guidelines. The aim of this study was to provide prevalence data on medication use before, during and after pregnancy in the Italian population. METHODS: A retrospective prevalence study using administrative healthcare databases was conducted. A cohort of 449,012 pregnant women (15-49 years) residing in eight Italian regions (59% of national population), who delivered in 2016-2018, were enrolled. The prevalence of medication use was estimated as the proportion (%) of pregnant women with any prescription. RESULTS: About 73.1% of enrolled women received at least one drug prescription during pregnancy, 57.1% in pre-pregnancy and 59.3% in postpartum period. The prevalence of drug prescriptions increased with maternal age, especially during the 1st trimester of pregnancy. The most prescribed medicine was folic acid (34.6%), followed by progesterone (19%), both concentrated in 1st trimester of pregnancy (29.2% and 14.8%, respectively). Eight of the top 30 most prescribed medications were antibiotics, whose prevalence was higher during 2nd trimester of pregnancy in women ≥ 40 years (21.6%). An increase in prescriptions of anti-hypertensives, antidiabetics, thyroid hormone and heparin preparations was observed during pregnancy; on the contrary, a decrease was found for chronic therapies, such as anti-epileptics or lipid-modifying agents. CONCLUSIONS: This study represents the largest and most representative population-based study illustrating the medication prescription patterns before, during and after pregnancy in Italy. The observed prescriptive trends were comparable to those reported in other European countries. Given the limited information on medication use in Italian pregnant women, the performed analyses provide an updated overview of drug prescribing in this population, which can help to identify critical aspects in clinical practice and to improve the medical care of pregnant and childbearing women in Italy.